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Unresectable Bladder Cancer
How I Manage Patients With Locally Advanced, Unresectable Bladder Cancer

Released: December 01, 2017

Expiration: November 30, 2018

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Most patients (approximately 75%) with bladder cancer present with nonmuscle-invasive early-stage disease. The remaining patients present with muscle-invasive bladder cancer, including disease that has not progressed beyond the bladder itself and has not progressed to the lymph nodes, with locally advanced disease that has progressed beyond the bladder to the surrounding tissue or lymph nodes, or with overt metastases. Patients with locally advanced, unresectable bladder cancer require a nuanced approach to treatment, distinct from approaches used for overt metastatic disease.

Locally advanced, unresectable disease includes patients with T4b tumors—disease that has extended outside the bladder to an adjacent structure such as the pelvic side wall—and patients with more advanced nodal disease (N2 or N3). According to the most recent American Joint Committee on Cancer (AJCC) staging system, these scenarios are considered stage IV, whereas N1 is defined as extension into 1 lymph node smaller than 2 cm and is now considered stage III. Based on the consensus, patients with a solitary lymph node between 1 and 2 cm are not definitively considered to have metastatic disease and should be treated with neoadjuvant chemotherapy followed by surgery with curative intent.

Patients with T4b disease, or those with N2 and N3 disease, require a different management approach because although their disease is contained within the anatomic area that is potentially resectable in the right hands, once bladder cancer has extended to those areas, cure with resection alone is highly unlikely. These scenarios are commonly considered “unresectable” due to the low chance of negative margins with surgery. This is the category we call locally advanced, unresectable bladder cancer, and in this commentary, I discuss the optimal treatment strategies for this subgroup of patients.

Standard Treatment Approach: Chemotherapy Followed by Surgery
Of importance, although cure is challenging to achieve for patients with locally advanced, unresectable disease, there remains a small but real chance of cure with aggressive platinum-based chemotherapy followed by consolidation. For this group of patients, I typically explain that although their cancer has spread, the chance of a cure is slim but not zero. To achieve cure, the patients must first safely get through approximately 6 cycles of platinum-based chemotherapy, demonstrate a radiographic response on imaging and/or biopsy, and proceed to surgery. Since T4a or N2/N3 disease is measurable, response is typically assessed after 3-4 cycles of chemotherapy, and if the cancer has diminished in size, we continue treatment with chemotherapy to consolidate this response, hoping to achieve a CR. For those patients who do achieve CR, surgery with curative intent can be cautiously recommended. At the time of surgery, if the pathology shows no residual cancer, those patients have an excellent long-term outlook. Unfortunately, imaging modalities to assess response are not perfect, and patients who appear to have a radiographic CR do not always have a pathologic CR. Therefore, the chance of cure with this treatment approach is estimated to be less than 10%—much lower than patients with stage II or III disease. Patients who do not achieve a pathologic CR (eg, those with residual cancer in the lymph nodes or who have residual positive margins) probably were not helped by the surgery. These patients should be followed closely for metastatic disease, as they are at high risk for recurrence.

Other Clinical Considerations: Alternative Approaches
Platinum-based chemotherapy is the standard of care for curative intent in this population based on robust response rates of approximately 70% and durable survival for some patients in earlier metastatic trials. But what about patients who are ineligible or may not be able to tolerate cisplatin-based chemotherapy? In this setting, although investigational and not yet proven, it is reasonable to use an immune checkpoint inhibitor with consideration of surgical resection/consolidation if a CR is achieved. There are some things we know about checkpoint inhibitors in this setting, but there is a lot that we do not know. What we know is that early results of first-line checkpoint inhibitors for patients with locally advanced, unresectable, cisplatin-ineligible disease have been promising: a 29% ORR for pembrolizumab (anti–PD-1) and 24% for atezolizumab (anti–PD-L1). Of importance, a subset of patients, less than 10% in each study, achieved a CR, which is necessary but not sufficient for cure with consolidative surgery. Theoretically, if a patient is cisplatin ineligible and has a CR, it would be reasonable to consider consolidative surgery. However, right now, we lack data—either prospective or retrospective—to determine whether this approach is effective. I think it is reasonable to consider checkpoint inhibition for patients with locally advanced unresectable disease who are ineligible for platinum agents, but I would not recommend a checkpoint inhibitor over platinum-based chemotherapy for eligible patients with locally advanced disease who may be cured with surgery.

Surgical Considerations
Whether patients have received pelvic radiation changes how they are subsequently treated, as it renders them ineligible for further radiation and significantly increases risks with cystectomy. For a patient with muscle-invasive disease that would otherwise be resectable, the standard of care of neoadjuvant treatment is still recommended and any subsequent surgery should be performed at a specialized site with surgeons experienced in this setting.

Understanding that the risks of surgery with previous radiation are significant, it may make sense to proceed with an immune checkpoint inhibitor and forgo major surgery. Given that the chance of cure in a locally advanced, unresectable tumor is low, in the setting of shared decision making, a patient may choose not to go through surgery and be treated as metastatic with ongoing checkpoint inhibition.

Patients with locally advanced unresectable disease who do not achieve a CR with chemotherapy or immunotherapy would not be candidates for surgery as it would incur significant risks, alter quality of life, and not likely affect the course of the disease. As mentioned, a radiographic CR is necessary but not sufficient to achieve cure in this setting. If patients received platinum-based chemotherapy, but at best achieve stable disease followed by progression or overt progression, they would be eligible for standard second-line options, such as 1 of the 5 currently approved checkpoint inhibitors: pembrolizumab, atezolizumab, nivolumab, durvalumab, and avelumab.

A New Tool to Help Guide Treatment Decisions for Patients With Urothelial Cancer
To help you address challenges with treatment decisions for your patients with bladder cancer, my colleagues—Matthew Galsky, MD; Matthew I. Milowsky, MD; Daniel P. Petrylak, MD; and Jonathan E. Rosenberg, MD—and I are creating a new treatment decision tool for bladder cancer, including patients with locally advanced disease. This online tool will help you select among the various treatment options for individual patients based on each patient’s specific characteristics by showing you recommendations from each of the experienced faculty listed above specifically for the patient information you enter into the tool. Check back in on the CCO Web site soon for this online tool, along with additional commentaries from the experts.

How have you coped with the challenge of treating patients with locally advanced and unresectable bladder cancer? Share your thoughts in the comment box below.

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In your clinic, have you used immune checkpoint inhibitors to treat patients with locally advanced, unresectable bladder cancer?
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